Journal article
Competition between α-actinin and Ca2+-Calmodulin Controls Surface Retention of the L-type Ca2+ Channel CaV1.2
Neuron (Cambridge, Mass.), Vol.78(3), pp.483-497
05/08/2013
DOI: 10.1016/j.neuron.2013.02.032
PMCID: PMC4570828
PMID: 23664615
Abstract
Regulation of neuronal excitability and cardiac excitation-contraction coupling requires the proper localization of L-type Ca2+ channels. We show that the actin-binding protein α-actinin binds to the C-terminal surface targeting motif of α11.2, the central pore-forming CaV1.2 subunit, in order to foster its surface expression. Disruption of α-actinin function by dominant-negative or small hairpin RNA constructs reduces CaV1.2 surface localization in human embryonic kidney 293 and neuronal cultures and dendritic spine localization in neurons. We demonstrate that calmodulin displaces α-actinin from their shared binding site on α11.2 upon Ca2+ influx through L-type channels, but not through NMDAR, thereby triggering loss of CaV1.2 from spines. Coexpression of a Ca2+-binding-deficient calmodulin mutant does not affect basal CaV1.2 surface expression but inhibits its internalization upon Ca2+ influx. We conclude that α-actinin stabilizes CaV1.2 at the plasma membrane and that its displacement by Ca2+-calmodulin triggers Ca2+-induced endocytosis of CaV1.2, thus providing an important negative feedback mechanism for Ca2+ influx.
•α-actinin binding to CaV1.2 IQ region maintains CaV1.2 surface and spine localization•Ca2+ influx via L channels, not NMDAR, displaces α-actinin from CaV1.2 via calmodulin•Ca2+ influx via L channels results in loss of CaV1.2 from dendritic spines•This Ca2+ influx causes rundown of L current by calmodulin-induced endocytosis
Prolonged Ca2+ influx into cells can be harmful if uncontrolled. Hall et al. show that L-type Ca2+ channels undergo endocytosis upon Ca2+ influx by displacing the structural protein α-actinin that determines its localization to proper surface sites.
Details
- Title: Subtitle
- Competition between α-actinin and Ca2+-Calmodulin Controls Surface Retention of the L-type Ca2+ Channel CaV1.2
- Creators
- Duane D Hall - Department of Pharmacology, University of Iowa, Iowa City, IA 52242, USAShuiping Dai - Department of Pharmacology, University of Iowa, Iowa City, IA 52242, USAPang-Yen Tseng - Department of Pharmacology, University of California, Davis, CA 95615Zulfiqar Malik - Department of Pharmacology, University of Iowa, Iowa City, IA 52242, USAMinh Nguyen - Department of Pharmacology, University of California, Davis, CA 95615Lucas Matt - Department of Pharmacology, University of California, Davis, CA 95615Katrin Schnizler - Department of Pharmacology, University of Iowa, Iowa City, IA 52242, USAAndrew Shephard - Department of Pharmacology, University of Iowa, Iowa City, IA 52242, USADurga P Mohapatra - Department of Pharmacology, University of Iowa, Iowa City, IA 52242, USAFuminori Tsuruta - Department of Neurobiology, Stanford University, Stanford, CA 94305, USARicardo E Dolmetsch - Department of Neurobiology, Stanford University, Stanford, CA 94305, USACarl J Christel - Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA 52242, USAAmy Lee - Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA 52242, USAAlain Burette - Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC 27599, USARichard J Weinberg - Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC 27599, USAJohannes W Hell - Department of Pharmacology, University of Iowa, Iowa City, IA 52242, USA
- Resource Type
- Journal article
- Publication Details
- Neuron (Cambridge, Mass.), Vol.78(3), pp.483-497
- Publisher
- Elsevier Inc
- DOI
- 10.1016/j.neuron.2013.02.032
- PMID
- 23664615
- PMCID
- PMC4570828
- ISSN
- 0896-6273
- eISSN
- 1097-4199
- Language
- English
- Date published
- 05/08/2013
- Academic Unit
- Molecular Physiology and Biophysics; Cardiovascular Medicine; Internal Medicine
- Record Identifier
- 9984094374302771
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